Trabecular bone adaptation plays a significant role in the etiology of many metabolic bone diseases such as osteoporosis, osteopetrosis, bone loss in microgravity and the long term success or failure of porous implants in total joint arthroplasty. Parathyroid hormone (PTH) is an important anabolic agent when administrated intermittently. The long- term goal of this research program is to use an in vivo model to study the biophysical signal transduction pathways mediating bone remodeling. In this proposed project, the trabecular bone response to combined mechanical loading and PTH stimulation will be quantified utilizing a novel in vivo rat tail vertebra model coupled with micro-CT image based finite element technique. Specifically, a controlled mechanical load will be applied to a rat tail vertebra and detailed 3D stress/strain environment in the trabecular bone tissue will be determined using an advanced finite element microstructural model of the same vertebra. The cellular response will be quantified using histomorphometric techniques in the presence or absence of intermittent PTH treatment. This approach will help to elucidate the separate and combined effects of mechanical and hormonal stimulations on bone cell response in vivo. The specific aims of this projects are: Specific Aim 1: To determine the in vivo cellular responses and 3D bone morphology to intermittent PTH treatment in rat tail vertebrae and their relationships to duration of treatment (2,4, and 8 weeks). Specific Aim 2: To determine the in vivo cellular responses and 3D bone morphology to mechanical stimulation in rat tail vertebrae and their relationship to loading levels (0 N:Immobilized, 100 N:Load and Sham), bone tissue stress/strain environment and duration of treatment (2,4, and 8 weeks). Specific Aim 3: To determine the in vivo cellular responses and 3D bone morphology to combined PTH treatment and mechanical stimulation in rat tail vertebrae and their relationships to sequence of stimulation (PTH- Load; Load-PTH; PTH-Immobilized; Immobilized-PTH; PTH-Sham; Sham-PTH), bone tissue stress/strain environment and duration of treatment (2,4, 8 weeks). Results from this pilot study may have significant implications with respect to the roles of mechanical forces and PTH in bone mass homeostasis.